Optimization of New Catalytic Topoisomerase II Inhibitors as an Anti-Cancer Therapy

Clinically used topoisomerase II (TOP2) inhibitors are poison inhibitors that induce DNA damage to cause cancer cell death. However, they can also destroy benign cells and thereby show serious side effects, including cardiotoxicity and drug-induced secondary malignancy. New TOP2 inhibitors with a di...

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Main Authors:	Victor M. Matias-Barrios, Mariia Radaeva, Chia-Hao Ho, Joseph Lee, Hans Adomat, Nada Lallous, Artem Cherkasov, Xuesen Dong
Format:	Article
Language:	English
Published:	MDPI AG 2021-07-01
Series:	Cancers
Subjects:	topoisomerase II catalytic inhibitor computer-aided drug design cytotoxicity DNA binding blocker
Online Access:	https://www.mdpi.com/2072-6694/13/15/3675

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spelling	doaj-b32d38e67ada4819814446a93510666a2021-08-06T15:20:06ZengMDPI AGCancers2072-66942021-07-01133675367510.3390/cancers13153675Optimization of New Catalytic Topoisomerase II Inhibitors as an Anti-Cancer TherapyVictor M. Matias-Barrios0Mariia Radaeva1Chia-Hao Ho2Joseph Lee3Hans Adomat4Nada Lallous5Artem Cherkasov6Xuesen Dong7The Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, 2660 Oak Street, Vancouver, BC V6H 3Z6, CanadaThe Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, 2660 Oak Street, Vancouver, BC V6H 3Z6, CanadaThe Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, 2660 Oak Street, Vancouver, BC V6H 3Z6, CanadaThe Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, 2660 Oak Street, Vancouver, BC V6H 3Z6, CanadaThe Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, 2660 Oak Street, Vancouver, BC V6H 3Z6, CanadaThe Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, 2660 Oak Street, Vancouver, BC V6H 3Z6, CanadaThe Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, 2660 Oak Street, Vancouver, BC V6H 3Z6, CanadaThe Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, 2660 Oak Street, Vancouver, BC V6H 3Z6, CanadaClinically used topoisomerase II (TOP2) inhibitors are poison inhibitors that induce DNA damage to cause cancer cell death. However, they can also destroy benign cells and thereby show serious side effects, including cardiotoxicity and drug-induced secondary malignancy. New TOP2 inhibitors with a different mechanism of action (MOA), such as catalytic TOP2 inhibitors, are needed to more effectively control tumor growth. We have applied computer-aided drug design to develop a new group of small molecule inhibitors that are derivatives of our previously identified lead compound T60. Particularly, the compound T638 has shown improved solubility and microsomal stability. It is a catalytic TOP2 inhibitor that potently suppresses TOP2 activity. T638 has a novel MOA by which it binds TOP2 proteins and blocks TOP2–DNA interaction. T638 strongly inhibits cancer cell growth, but exhibits limited genotoxicity to cells. These results indicate that T638 is a promising drug candidate that warrants further development into clinically used anticancer drugs.https://www.mdpi.com/2072-6694/13/15/3675topoisomerase IIcatalytic inhibitorcomputer-aided drug designcytotoxicityDNA binding blocker
collection	DOAJ
language	English
format	Article
sources	DOAJ
author	Victor M. Matias-Barrios Mariia Radaeva Chia-Hao Ho Joseph Lee Hans Adomat Nada Lallous Artem Cherkasov Xuesen Dong
spellingShingle	Victor M. Matias-Barrios Mariia Radaeva Chia-Hao Ho Joseph Lee Hans Adomat Nada Lallous Artem Cherkasov Xuesen Dong Optimization of New Catalytic Topoisomerase II Inhibitors as an Anti-Cancer Therapy Cancers topoisomerase II catalytic inhibitor computer-aided drug design cytotoxicity DNA binding blocker
author_facet	Victor M. Matias-Barrios Mariia Radaeva Chia-Hao Ho Joseph Lee Hans Adomat Nada Lallous Artem Cherkasov Xuesen Dong
author_sort	Victor M. Matias-Barrios
title	Optimization of New Catalytic Topoisomerase II Inhibitors as an Anti-Cancer Therapy
title_short	Optimization of New Catalytic Topoisomerase II Inhibitors as an Anti-Cancer Therapy
title_full	Optimization of New Catalytic Topoisomerase II Inhibitors as an Anti-Cancer Therapy
title_fullStr	Optimization of New Catalytic Topoisomerase II Inhibitors as an Anti-Cancer Therapy
title_full_unstemmed	Optimization of New Catalytic Topoisomerase II Inhibitors as an Anti-Cancer Therapy
title_sort	optimization of new catalytic topoisomerase ii inhibitors as an anti-cancer therapy
publisher	MDPI AG
series	Cancers
issn	2072-6694
publishDate	2021-07-01
description	Clinically used topoisomerase II (TOP2) inhibitors are poison inhibitors that induce DNA damage to cause cancer cell death. However, they can also destroy benign cells and thereby show serious side effects, including cardiotoxicity and drug-induced secondary malignancy. New TOP2 inhibitors with a different mechanism of action (MOA), such as catalytic TOP2 inhibitors, are needed to more effectively control tumor growth. We have applied computer-aided drug design to develop a new group of small molecule inhibitors that are derivatives of our previously identified lead compound T60. Particularly, the compound T638 has shown improved solubility and microsomal stability. It is a catalytic TOP2 inhibitor that potently suppresses TOP2 activity. T638 has a novel MOA by which it binds TOP2 proteins and blocks TOP2–DNA interaction. T638 strongly inhibits cancer cell growth, but exhibits limited genotoxicity to cells. These results indicate that T638 is a promising drug candidate that warrants further development into clinically used anticancer drugs.
topic	topoisomerase II catalytic inhibitor computer-aided drug design cytotoxicity DNA binding blocker
url	https://www.mdpi.com/2072-6694/13/15/3675
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Optimization of New Catalytic Topoisomerase II Inhibitors as an Anti-Cancer Therapy

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